Anticonvulsant derivatives useful in treating manic-depressive bipolar disorder

ABSTRACT

This application relates to the use of topiramate and related sulfonamides for the treatment of manic-depressive bipolar disorder.

This application claims priority to provisional application No.60/020,850, filed Jun. 28, 1996.

BACKGROUND OF THE INVENTION

Compounds of Formula I: ##STR1## are structurally novel antiepilepticcompounds that are highly effective anticonvulsants in animal tests(Maryanoff, B. E, Nortey, S. O., Gardocki, J. F., Shank, R. P. andDodgson, S. P. J. Med. Chem. 30, 880-887, 1987; Maryanoff, B. E.,Costanzo, M. J., Shank, R. P., Schupsky, J. J., Ortegon, M. E., andVaught J. L. Bioorganic & Medicinal Chemistry Letters 3,2653-2656, 1993,McComsey, D. F. and Maryanoff, B. E., J. Org. Chem. 1995). Thesecompounds are covered by three U.S. Pat. Nos.: 4,513,006, 5,384,327 and5,498,629. One of these compounds2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate known astopiramate has been demonstrated in clinical trials of human epilepsy tobe effective as adjunctive therapy or as monotherapy in treating simpleand complex partial seizures and secondarily generalized seizures (E.FAUGHT, B. J. WILDER, R. E. RAMSEY, R. A. REIFE, L D. KRAMER, G. W.PLEDGER, R. M. KARIM et. al., Epilepsia 36 (S4) 33, 1995; S. K. SACHDEO,R. C. SACHDEO, R. A. REIFE, P. LIM and G. PLEDGER, Epilepsia 36 (S4) 33,1995), and is currently marketed for the treatment of simple and complexpartial seizure epilepsy with or without secondary generalized seizuresin Great Britain, Finland, the United States and Sweden and applicationsfor regulatory approval are presently pending in numerous countriesthroughout the world.

Compounds of Formula I were initially found to possess anticonvulsantactivity in the traditional maximal electroshock seizure (MES) test inmice (SHANK, R. P., GARDOCKI, J. F., VAUGHT, J. L., DAVIS, C. B.,SCHUPSKY, J. J., RAFFA, R. B., DODGSON, S. J., NORTEY, S. O., andMARYANOFF, B. E., Epilepsia 35 450-460, 1994). Subsequent studiesrevealed that Compounds of Formula I were also highly effective in theMES test in rats. More recently topiramate was found to effectivelyblock seizures in several rodent models of epilepsy (J. NAKAMURA, S.TAMURA, T. KANDA, A. ISHII, K. ISHIHARA, T. SERIKAWA, J. YAMADA, and M.SASA, Eur. J. Pharmacol. 254 83-89, 1994), and in an animal model ofkindled epilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24, 73-77,1996).

Recent preclinical studies on topiramate have revealed previouslyunrecognized pharmacological properties which suggest that topiramateshould be effective in treating manic-depressive bipolar disorder(MDBD).

DISCLOSURE OF THE INVENTION

Accordingly, it has been found that compounds of the following formulaI: ##STR2## wherein X is O or CH₂, and R₁, R₂, R₃, R₄ and R₅ are asdefined hereinafter are useful in treating manic-depressive bipolardisorder (MDBD).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The sulfamates of the invention are of the following formula (I):##STR3## wherein X is CH₂ or oxygen;

R₁ is hydrogen or alkyl; and

R₂, R₃, R₄ and R₅ are independently hydrogen or lower alkoxy, when X isoxygen, R₂ and R₃ and/or R₄ and R₅ together may be a methylenedioxygroup of the following formula (II): ##STR4## wherein R₆ and R₇ are thesame or different and are hydrogen, lower alkyl or are alkyl and arejoined to form a cyclopentyl or cyclohexyl ring.

R₁ in particular is hydrogen or alkyl of about 1 to 4 carbons, such asmethyl, ethyl and iso-propyl. Alkyl throughout this specificationincludes straight and branched chain alkyl. Alkyl groups for R₂, R₃, R₄,R₅, R₆ and R₇ are of about 1 to 3 carbons and include methyl, ethyl,iso-propyl and n-propyl.

A particular group of compounds of formula (I) are those wherein X isoxygen and both R₂ and R₃, and R₄ and R₅ together are methylenedioxygroups of the formula (II), wherein R₆ and R₇ are both hydrogen, bothalkyl, or combine to form a spiro cyclopentyl or cyclohexyl ring, inparticular where R₆ and R₇ are both alkyl such as methyl. A second groupof compounds are those wherein X is CH₂ and R₄ and R₅ are joined to forma benzene ring. A third group of compounds of formula (I) are thosewherein both R₂ and R₃ are hydrogen.

The compounds of formula (I) may be synthesized by the followingmethods:

(a) Reaction of an alcohol of the formula RCH₂ OH with a chlorosulfamateof the formula CISO₂ NH₂ or CISO₂ NHR₁ in the presence of a base such aspotassium a-butoxide or sodium hydride at a temperature of about -20° to25° C. and in a solvent such as toluene, THF or dimethylformamidewherein R is a moiety of the following formula (III): ##STR5## (b)Reaction of an alcohol of the formula RCH₂ OH with sulfurylchloride ofthe formula SO₂ Cl₂ in the presence of a base such as triethylamine orpyridine at a temperature of about -40° to 25° C. in a solvent such asdiethyl ether or methylene chloride to produce a chlorosulfate of theformula RCH₂ OSO₂ Cl.

The chlorosulfate of the formula RCH₂ OSO₂ Cl may then be reacted withan amine of the formula R₁ NH₂ at a temperature of abut 40° to 25° C. ina solvent such as methylene chloride or acetonitrile to produce acompound of formula (I). The reaction conditions for (b) are alsodescribed by T. Tsuchiya et al. in Tet. Letters, No. 36, p. 3365 to 3368(1978).

(c) Reaction of the chlorosulfate RCH₂ OSOCl with a metal azide such assodium azide in a solvent such as methylene chloride or acetonitrileyields an azidosulfate of the formula RCH₂ OSO₂ N₃ as described by M.Hedayatullah in Tet. Lett. p. 2455-2458 (1975). The azidosulfate is thenreduced to a compound of formula (I) wherein R₁ is hydrogen by catalytichydrogenation, e.g. with a noble metal and H₂ or by heating with coppermetal in a solvent such as methanol.

The starting materials of the formula RCH₂ OH may be obtainedcommercially or as known in the art. For example, starting materials ofthe formula RCH₂ OH wherein both R₂ and R₃, and R₄ and R₅ are identicaland are of the formula (II) may be obtained by the method of R. F. Bradyin Carbohydrate Research, Vol.14, p. 35 to 40 (1970) or by reaction ofthe trimethylsilyl enol ether of a R₆ COR₇ ketone or aldehyde withfructose at a temperature of about 25° C., in a solvent such ahalocarbon, e.g. methylene chloride in the presence of a protic acidsuch as hydrochloric acid or a Lewis Acid such as zinc chloride. Thetrimethylsilyl enol ether reaction is described by G. L. Larson et al inJ. Org. Chem. Vol. 38, No. 22, p. 3935 (1973).

Further, carboxylic acids and aldehydes of the formulae RCOOH and RCHOmay be reduced to compounds of the formula RCH₂ OH by standard reductiontechniques, e.g. reaction with lithium aluminum hydride, sodiumborohydride or borane-THF complex in an inert solvent such a diglyme,THF or toluene at a temperature of about 0° to 100° C., e.g. asdescribed by H. O. House in "Modern Synthetic Reactions", 2nd Ed., pages45 to 144 (1972).

The compounds of formula I: may also be made by the process disclosedU.S. Pat. No.: 4,513,006, which is incorporated by reference herein.

The compounds of formula I include the various individual isomers aswell as the racemates thereof, e.g., the various alpha and betaattachments, i.e., below and above the plane of the drawing, of R₂, R₃,R₄ and R₅ on the 6-membered ring. Preferably, the oxygens of themethylenedioxy group (II) are attached on the same side of the6-membered ring.

Manic-depressive bipolar disorder is a progressive psychiatric disorderof unknown etiology (F. GOODWIN and K. R. JAMISON, Manic-DepressiveIllness, Oxford University Press, New York, 1990).; however, recurrencesof manic-depressive illness have been hypothesized to be caused byelectrophysiologic kindling (F. GOODWIN and K. R. JAMISON,Manic-Depressive Illness, Oxford University Press, New York, pp 405-407,1990). Topiramate has been shown to be effective in blocking kindledseizures in rats; A. WAUQUIER and S. ZHOU, Epilepsy Res. 24 73-77, 1996in press).

For treating manic-depressive bipolar disorder, a compound of formula(I) may be employed at a daily dosage in the range of about 50 to 200mg, usually in two divided doses, for an average adult human. A unitdose would contain about 25 to 100 mg of the active ingredient.

To prepare the pharmaceutical compositions of this invention, one ormore sulfamate compounds of formula (I) are intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral, by suppository, or parenteral. In preparing the compositions inoral dosage form, any of the usual pharmaceutical media may be employed.Thus, for liquid oral preparations, such as for example, suspensions,elixirs and solutions, suitable carriers and additives include water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like; for solid oral preparations such as, for example,powders, capsules and tablets, suitable carriers and additives includestarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. Suppositories may be prepared, in whichcase cocoa butter could be used as the carrier. For parenterals, thecarrier will usually comprise sterile water, though other ingredients,for example, for purposes such as aiding solubility or for preservation,may be included. Injectable suspensions may also be prepared in whichcase appropriate liquid carriers, suspending agents and the like may beemployed. Topiramate is currently available for oral administration inround tablets containing 25 mg, 100 mg or 200 mg of active agent. Thetablets contain the following inactive ingredients: lactose hydrous,pregelatinized starch, microcrystalline cellulose, sodium starchglycolate, magnesium stearate, purified water, carnauba wax,hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol,synthetic iron oxide, and polysorbate 80.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder injection, teaspoonful, suppository andthe like from about 25 to about 100 mg of the active ingredient.

What is claimed is:
 1. A method for treating Manic-depressive bipolardisorder comprising administering to a mammal afflicted with suchcondition a therapeutically effective amount for treating such conditionof a compound of the formula I: ##STR6## wherein X is CH₂ or oxygen;R₁is hydrogen or alkyl; and R₂, R₃, R₄ and R₅ are independently hydrogenor lower alkyl; when X is oxygen, R₂ and R₃ and/or R₄ and R₅ togethermay be a methylenedioxy group of the following formula (II): ##STR7##wherein R₆ and R₇ are the same or different and are hydrogen, loweralkyl or are alkyl and are joined to form a cyclopentyl or cyclohexylring.
 2. The method of claim 1 wherein the compound of formula I istopiramate.
 3. The method of claim 1, wherein the therapeuticallyeffective amount is of from about 50 to 200 mg.
 4. The method of claim1, wherein the amount is of from about 25 to 100 mg.